Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:17]([Cl:18])=[CH:16][C:12]([C:13]([NH2:15])=O)=[CH:11][C:10]=2[Cl:19])=[CH:4][CH:3]=1.B>O1CCCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[C:17]([Cl:18])=[CH:16][C:12]([CH2:13][NH2:15])=[CH:11][C:10]=2[Cl:19])=[CH:6][CH:7]=1
Reactant: NC(=O)c1cc(Cl)c(Sc2ccc(Cl)cc2)c(Cl)c1
Agent: B
Solvent: C1CCOC1
Product: Cl
Product: NCc1cc(Cl)c(Sc2ccc(Cl)cc2)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 162.5 %

Procedure:
A solution of 4-(4-chlorophenylthio)-3,5-dichlorobenzamide (25.7 g, 77.3 mmol) in tetrahydrofuran (155 ml) was added dropwise over 25 minutes to a stirred 1.0M solution of borane in tetrahydrofuran (232 ml) at ambient temperature under nitrogen atmosphere. The mixture was refluxed for 16 hours, cooled to 0° C., and quenched by addition of 2.0N hydrochloric acid. Solvent was evaporated under vacuum and the residue treated with water (400 ml) and diethyl ether. The mixture was basified with 2.5N aqueous sodium hydroxide, the phases were separated, and the aqueous phase extracted twice with diethyl ether. The combined extracts were washed with water (2X) and brine, dried over anhydrous magnesium sulfate, and evaporated under vacuum. The residual oil was dissolved in methanol (500 ml), treated with concentrated hydrochloric acid, and evaporated to dryness at 50° C. under vacuum. The residue was azeotroped twice with methanol, stirred 30 minutes with diethyl ether (300.ml), filtered, washed with diethyl ether (4X), and dried at 40° C. under vacuum to provide 22.3 g (81%) of 4-(4-chlorophenylthio)-3,5-dichlorobenzylamine hydrochloride, m.p. 217°-219° C. The free base was liberated by suspending the salt (4.0 g) in water, basifying with dilute aqueous sodium hydroxide, and extracting with diethyl ether (3X). The combined extracts were washed with water (2X) and brine, dried over anhydrous magnesium sulfate, and evaporated under vacuum to provide 3.59 g (100%) of oily free base.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]#[C:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12].[C:14]([O:18][C:19]([N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([CH2:31][CH2:32][O:33][C:34]3[CH:35]=[C:36]4[C:40](=[CH:41][CH:42]=3)[NH:39][CH:38]=[CH:37]4)[N:29]=2)[CH2:24][CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([CH2:31][CH2:32][O:33][C:34]3[CH:35]=[C:36]4[C:40](=[CH:41][CH:42]=3)[N:39]([C:5]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[Cl:12])=[CH:4][C:3]([O:2][CH3:1])=[O:13])[CH:38]=[CH:37]4)[N:29]=2)[CH2:24][CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCCc2ccc(CCOc3ccc4[nH]ccc4c3)nc21
Reactant: COC(=O)C#Cc1ccccc1Cl
Product: COC(=O)C=C(c1ccccc1Cl)n1ccc2cc(OCCc3ccc4c(n3)N(C(=O)OC(C)(C)C)CCC4)ccc21
Yield: 43 %

Procedure:
The title compound was synthesized from (2-chloro-phenyl)-propynoic acid methyl ester and 7-[2-(1H-Indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester using the procedure described in Example 16, step (d1), in 43% yield as an E/Z isomeric mixture. 1H NMR (CDCl3) [E/Z mixture] δ 7.54-7.30 (m, 6H), 7.18 (m, 1H), 6.95 (m, 1H), 6.83 (m, 1H), 6.68-6.50 (m, 2H), 6.35 (s, 0.33H), 5.95 (s, 0.67H), 4.39 (m, 2H), 3.78 (m, 2H), 3.64 (s, 3H), 3.22 (m, 2H), 2.73 (m, 2H), 1.92 (m, 2H) 1.52 (s, 9H). Mass Spectrum (LCMS, ESI) calculated for C28H27ClN3O3 488.2 (M-Boc+H); found 488.4.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][NH:11][C:12]2[S:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[H-].[Na+].[CH3:23]N(C)C=O.IC>O>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([CH2:10][N:11]([C:12]2[S:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)[CH3:23])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(=O)N1CCC(CNc2nc3ccccc3s2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CC(=O)N1CCC(CN(C)c2nc3ccccc3s2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
A mixture of 8.7 parts of 1-acetyl-N-(2-benzothiazolyl)-4-piperidinemethanamine, 1.44 parts of a sodium hydride dispersion 60% and 270 parts of N,N-dimethylformamide was stirred for 1 hour at room temperature. 5.48 Parts of iodomethane were added dropwise slowly. Upon completion, stirring was continued overnight at room temperature. The reaction mixture was poured into water. The product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated in vacuo. The residue was purified by column chromatography (HPLC) over silica gel using a mixture of dichloromethane and methanol (98.75:1.25 by volume) as eluent. The second faction was collected and the eluent was evaporated, yielding 7.6 parts (84%) of 1-acetyl-N-(2-benzothiazolyl)-N-methyl-4-piperidinemethanamine as a residue (intermediate 52).
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]([CH2:27][CH3:28])[C:16]3[C:21]([C:22]=2[C:23]#[N:24])=[CH:20][CH:19]=[C:18]([O:25][CH3:26])[CH:17]=3)=[CH:10][CH:9]=1)=[O:6].[OH-].[K+]>CO>[CH2:27]([N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[C:18]([O:25][CH3:26])[CH:17]=2)[C:22]([C:23]#[N:24])=[C:14]1[C:11]1[CH:12]=[CH:13][C:8]([N:7]2[CH2:2][CH2:3][NH:4][C:5]2=[O:6])=[CH:9][CH:10]=1)[CH3:28]
Reactant: CCn1c(-c2ccc(NC(=O)NCCCl)cc2)c(C#N)c2ccc(OC)cc21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCn1c(-c2ccc(N3CCNC3=O)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 49 °C
Reaction time: 24 h
Yield: 61.7 %

Procedure:
To a solution of 1-(2-chloroethyl)-3-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-urea (100 mg, 0.252 mmol) in MeOH (10 mL) was added aqueous 1M KOH (504 uL) and then stirred at 49° C. for 24 h. The solvents were removed under reduced pressure. The residue was diluted with ethyl acetate and then washed with water. The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was diluted with ethyl acetate and then triturated with hexane and the precipitate collected by filtration and washed well with 50% ethyl acetate in hexane and dried in vacuo to afford 1-ethyl-6-methoxy-2-[4-(2-oxo-imidazolidin-1-yl)-phenyl]-1H-indole-3-carbonitrile (56 mg, 62%).
Reaction SMILES: [CH:1]([N:5]1[C:9]2[CH:10]=[C:11]([N:15]3[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[NH:17][C:16]3=[O:26])[C:12]([F:14])=[CH:13][C:8]=2[S:7][C:6]1=[O:27])([CH2:3][CH3:4])[CH3:2].CI.[C:30](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:1]([N:5]1[C:9]2[CH:10]=[C:11]([N:15]3[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:23])([F:25])[F:24])[N:17]([CH3:30])[C:16]3=[O:26])[C:12]([F:14])=[CH:13][C:8]=2[S:7][C:6]1=[O:27])([CH2:3][CH3:4])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCC(C)n1c(=O)sc2cc(F)c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)cc21
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CCC(C)n1c(=O)sc2cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc21
Yield: 48.3 %

Procedure:
To a solution of 1-[3-sec-butyl-6-fluoro-2 (3H)benzothiazolon-5-yl]-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidine-2,6-dione (2.0 g) in dimethylformamide (10 g), methyl iodide (0.5 g) and potassium carbonate (1.6 g) were added, and the resultant mixture was heated at 40° to 80° C. for 3 hours. After completion of the reaction, the reaction mixture was poured into water, and the precipitated crystals were collected by filtraction, washed and dried. The residue was purified by column chromatography to give 1-[3-sec-butyl-6-fluoro-2(3H) -benzothiazolon-5-yl]-3-metyl -4-trifluoromethyl-1,2,3,6-tetrahydropyrimidine-2,6-dione (1.0 g ).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([NH2:11])[C:8]([NH:12][CH3:13])=[CH:7][C:6]=1[F:14])[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1[N:24]=[C:25]=[S:26]>CO.C(#N)C>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([NH:11][C:25]([NH:24][C:18]2[C:19]([Cl:23])=[CH:20][CH:21]=[CH:22][C:17]=2[Cl:16])=[S:26])[C:8]([NH:12][CH3:13])=[CH:7][C:6]=1[F:14])[CH3:2]
Reactant: CCOC(=O)c1cc(N)c(NC)cc1F
Reactant: S=C=Nc1c(Cl)cccc1Cl
Solvent: CC#N
Solvent: CO
Product: CCOC(=O)c1cc(NC(=S)Nc2c(Cl)cccc2Cl)c(NC)cc1F

Procedure:
Prepared analogously to example 131d from 5-amino-2-fluoro-4-methylamino-benzoic acid ethyl ester and 1,3-dichloro-2-isothiocyanato-benzene in methanol and acetonitrile.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[N:21]1([C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=2)[CH:30]=O)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:30][C:29]2[CH:32]=[CH:33][CH:34]=[C:27]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:28]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cccc(N2CCCCC2)c1
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1cccc(N2CCCCC2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with commercially available 3-(piperidin-1-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.61 min.; [M+H]+: 409.11 g/mol.
Reaction SMILES: [Li]CCCC.[CH3:6][O:7][C:8]1[CH:20]=[CH:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C:10]=2[CH:9]=1.Br[CH2:22][CH2:23][CH:24]1[O:28][CH2:27][CH2:26][O:25]1.CCOC(C)=O>C1COCC1.CCCCCC>[CH3:6][O:7][C:8]1[CH:20]=[CH:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([CH2:22][CH2:23][CH:24]3[O:28][CH2:27][CH2:26][O:25]3)[C:10]=2[CH:9]=1
Reactant: BrCCC1OCCO1
Reactant: COc1ccc2c(c1)Cc1ccccc1-2
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(CCC1OCCO1)c1ccccc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.3 %

Procedure:
A solution of n-BuLi (2.5 M in hexane, 6.4 mL, 16.0 mmol) was slowly added into a cooled (-78° C.) solution of 2-methoxyfluorene (prepared according to example 10; 3.1 g, 15.8 mmol) in 100 ml THF. The reaction mixture became dark red and a solid started to precipitate out. After 30 minutes 2-(2-bromoethyl)-1,3-dioxolane (5.8 g, 32.0 mmol) was added to the cold solution and the solution was warmed up to room temperature. The reaction mixture was stirred overnight at room temperature. TLC (silica, 25% EtOAc in hexane) was used to monitor the reaction. The reaction was quenched with water and the product was extracted into EtOAc. The organic layer was washed with water (×3), dried over magnesium sulfate and evaporated. Short path chromatography (5% ethyl acetate/hexane) afforded 3.2 g (62.5%) of the product.
Reaction SMILES: [Na].Cl[C:3]1[NH:8][C:7](=[O:9])[C:6]([F:10])=[CH:5][N:4]=1.[CH2:11]([OH:15])[CH2:12][CH2:13][CH3:14]>>[CH2:11]([O:15][C:3]1[NH:8][C:7](=[O:9])[C:6]([F:10])=[CH:5][N:4]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCO
Reactant: O=c1[nH]c(Cl)ncc1F
Agent: [Na]
Product: CCCCOc1ncc(F)c(=O)[nH]1
Yield: 91.9 %

Procedure:
A 5.8 g quantity of metal sodium is dissolved in 300 ml of absolute n-butanol, 14.9 g of 2-chloro-5-fluoropyrimidin-4-one is added to the solution and the mixture is heated in a sealed tube at 140° to 150° C for 5 hours for reaction. The solvent is distilled off from the reaction mixture, 50 ml of water is added to the residue and the pH of the mixture is adjusted to 4-5 to separate out crystals, which are recrystallized from ethanol to give 17.1 g of white crystalline 2-n-butoxy-5-fluoropyrimidin-4-one in a yield of 91.9%, m.p. 127°-129° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:31])[CH2:3][C@H:4]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[N:12]([CH3:21])[C:11]=2[CH:22]=1.[Br:32]N1C(=O)CCC1=O>C(#N)C.O>[Br:32][C:8]1[C:7]([O:6][CH2:5][C@@H:4]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:3][CH:2]([CH3:31])[CH3:1])=[CH:22][C:11]2[N:12]([CH3:21])[C:13](=[O:20])[C:14]3[C:19]([C:10]=2[CH:9]=1)=[CH:18][CH:17]=[N:16][CH:15]=3
Reactant: CC(C)C[C@@H](COc1ccc2c3ccncc3c(=O)n(C)c2c1)NC(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CC#N
Product: CC(C)C[C@@H](COc1cc2c(cc1Br)c1ccncc1c(=O)n2C)NC(=O)OC(C)(C)C
Temperature: 85 °C
Yield: 67.7 %

Procedure:
To a solution of (S)-tert-butyl (4-methyl-1-((6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)pentan-2-yl)carbamate (0.100 g, 0.235 mmol) (as prepared in Ex. 2, Part D) in anhydrous acetonitrile (5 mL) was added N-bromosuccinimide (0.042 g, 0.235 mmol) and the mixture was heated at 85° C. for 5 h. The reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (2×20 mL). The combined organic layers were dried over sodium sulfate and evaporated under reduced pressure to afford crude product which was purified by preparative TLC (gradient of ethyl acetate and petroleum ether) to afford (S)-tert-butyl (1-((9-bromo-6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (80 mg, 0.159 mmol, 68% yield) as an off-white solid. LC/MS (ESI) m/e 504.2 [(M+H)+, calcd for C24H31BrN3O4 504.1]; LC/MS retention time (method A): tR=2.23 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([F:17])[CH:16]=1)[CH2:5][P:6](=[O:13])([O:10]CC)[O:7]CC.Br[Si](C)(C)C.O>ClCCl.CO>[F:17][C:15]1[CH:14]=[C:4]([CH:3]=[C:2]([F:1])[CH:16]=1)[CH2:5][P:6](=[O:7])([OH:13])[OH:10]
Reactant: CCOP(=O)(Cc1cc(F)cc(F)c1)OCC
Agent: C[Si](C)(C)Br
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: O=P(O)(O)Cc1cc(F)cc(F)c1
Reaction time: 6 h
Yield: 83.5 %

Procedure:
Diethyl 3,5-difluorobenzylphosphonate (3.00 g, 11.4 mmol) was dissolved in dry dichloromethane (25 mL). Bromotrimethylsilane (4.9 mL, 37 mmol) was added via syringe. The reaction was capped with a greased glass stopper and allowed to stir for 6 hours. The volatiles were removed under reduced pressure to yield a yellow oil. This was dissolved in 8:1 methanol:water (25 mL) and allowed to stir overnight. After removing the solvents, recrystallization in acetonitrile yielded a white crystalline solid (1.98 g, 91% yield). 1H NMR (400.14 MHz, DMSO) δ 7.05 (dt, J=9.49, 2.09 Hz), 6.95 (d, J=8.54 Hz, 2H), 3.02 (d, J=21.57 Hz, 2H). 31P {1H} NMR (161.97 MHz, DMSO): δ 20.63. Analysis calculated (found) %: C, 40.40 (40.67), H, 3.39 (3.39).
Reaction SMILES: [H-].[Na+].[O:3]1CC[CH2:5][CH2:4]1.C([C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[CH2:13][CH2:14][CH:15]([N:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])[CH2:16]2)(=O)C.[CH3:28][N:29](C)C=O>>[C:4]([N:29]([C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[CH2:13][CH2:14][CH:15]([N:21]([CH2:22][CH2:23][CH3:24])[CH2:25][CH2:26][CH3:27])[CH2:16]2)[CH3:28])(=[O:3])[CH3:5]
Reactant: CCCN(CCC)C1CCc2c(cccc2C(C)=O)C1
Reactant: C1CCOC1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CCCN(CCC)C1CCc2c(cccc2N(C)C(C)=O)C1

Procedure:
0.38 g of a 75% suspension of sodium hydride in paraffin oil (0.012 mol) are added to a mixture of 40 ml of absolute dimethylformamide and 5 ml of absolute tetrahydrofuran. Then 2.88 g (0.010 mol) of 5-acetyl-2-di-n-propylamino-tetraline (Example 4.3.4) dissolved in 10 ml of absolute dimethylformamide are added with stirring and cooling with ice. Then the mixture is stirred at ambient temperature until the reaction is complete (several hours; monitored by DC). After concentration by rotary evaporation, finally at 95° C. under a complete water-jet vacuum, the residue is shaken with 50 ml of water and 50 ml of methylene chloride. The aqueous phase separated off is extracted twice more with 15 ml of methylene chloride. The combined extracts are washed with 20 ml of water, dried with sodium sulphate and, after the drying agent has been filtered off, concentrated by rotary evaporation, finally at 80° C. under a complete water-jet vacuum. The residue cannot be crystallised either as a base or as a salt. Therefore it is purified by column chromatography on 150 g of silica gel with methylene chloride/methanol/conc. ammonia 90:10:0.5. The substance purified in this way (2.8 g, 92.6% of theory) does not crystallise either, even though it is pure according to thin layer chromatography (silica gel, above-mentioned mixture of solvents, Rf =0.64) and by NMR spectroscopy.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:30])/[CH:14]=[CH:15]/[C:16]3[C:17]([NH:26][C:27](=[O:29])[CH3:28])=[CH:18][C:19]4[C:24]([CH:25]=3)=CC=CC=4)[C@H:9]([CH3:31])[CH2:8]2)=[CH:4][CH:3]=1.CCN(CC)CC.C([Cl:44])(=O)C.C1C[O:48][CH2:47][CH2:46]1>C(=O)([O-])[O-].[Na+].[Na+]>[Cl:44][C:19]1[C:24]([O:48][CH2:47][CH3:46])=[CH:25][C:16](/[CH:15]=[CH:14]/[C:13]([N:10]2[CH2:11][CH2:12][N:7]([CH2:6][C:5]3[CH:32]=[CH:33][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:8][C@H:9]2[CH3:31])=[O:30])=[C:17]([NH:26][C:27](=[O:29])[CH3:28])[CH:18]=1
Reactant: CC(=O)Cl
Reactant: CC(=O)Nc1cc2ccccc2cc1/C=C/C(=O)N1CCN(Cc2ccc(F)cc2)C[C@H]1C
Reactant: C1CCOC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Product: CCOc1cc(/C=C/C(=O)N2CCN(Cc3ccc(F)cc3)C[C@H]2C)c(NC(C)=O)cc1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 81 %

Procedure:
(E)-3-(2-Amino-4-chloro-5-ethoxyphenyl)-1-[(R)-4-(4-fluorobenzyl)-2-meyhyl-piperazin-1-yl]-propenone (prepared by amide coupling and SnCl2 reduction as described in example 30) (0.1 g, 0.23 mmol) was dissolved in 10 ml THF and 38.7 μl (0.28 mmol) NEt3 and 16.5 μl (0.23 mmol) acetyl chloride were added. This mixture was stirred for 20 min. at room temperature. Then the mixture was diluted with 10 ml saturated sodium carbonate solution and extracted with ethyl acetate. The title compound was purified by chromatography (SiO2, ethyl acetate/MeOH/NH3conc. 95/5/0.5) and was isolated as a pale solid (89 mg, 81%)
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12][C:6]=2[C:5]([CH:14]=O)=[CH:4][CH:3]=1.C1(P(=CC=[O:37])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:38]1(C)C=C[CH:41]=[CH:40][CH:39]=1>>[Cl:1][C:2]1[C:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12][C:6]=2[C:5]([CH:14]=[CH:38][CH:39]=[CH:40][CH:41]=[O:37])=[CH:4][CH:3]=1
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CN1CCc2c(Cl)ccc(C=O)c2CC1
Reactant: Cc1ccccc1
Product: CN1CCc2c(Cl)ccc(C=CC=CC=O)c2CC1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A solution of 9-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine-6-carboxaldehyde, prepared as in Example 12, (2.2 g, 10 mmol) in toluene (15 ml) was treated with triphenylphosphoranylideneacetaldehyde (4.4 g, 14 mmol) and stirred at 100° C. for 24 hours. The mixture was concentrated and the residue was triturated with ethyl ether-petroleum ether (4:1) and the supernatant concentrated to give 3 g of 5-(9-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepin-6-yl)-2,4-pentadienal.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][NH2:6])[CH3:2].[ClH:9].[Cl:10][C:11]([N:13]1[C:19]2[S:20][C:21]([CH2:23][CH3:24])=[CH:22][C:18]=2[C:17]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])=[N:16][CH2:15][CH2:14]1)=[O:12]>O1CCCC1>[OH2:12].[ClH:10].[ClH:9].[Cl:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:17]1[C:18]2[CH:22]=[C:21]([CH2:23][CH3:24])[S:20][C:19]=2[N:13]([C:11](=[O:12])[NH:6][CH2:5][CH2:4][N:3]([CH2:7][CH3:8])[CH2:1][CH3:2])[CH2:14][CH2:15][N:16]=1
Reactant: CCc1cc2c(s1)N(C(=O)Cl)CCN=C2c1ccccc1Cl
Reactant: CCN(CC)CCN
Agent: Cl
Solvent: C1CCOC1
Product: CCc1cc2c(s1)N(C(=O)NCCN(CC)CC)CCN=C2c1ccccc1Cl
Product: O
Temperature: 0 °C

Procedure:
To a solution of 9.3 g of 2-diethylaminoethylamine in 50 ml of tetrahydrofuran is added 7.8 g of 1-chlorocarbonyl-5-o-chlorophenyl-7-ethyl-2,3-dihydro-1H-thieno[2,3-e][1,4]diazepine hydrochloride by portions with cooling and stirring. After the mixture is reacted for 2 hours at room temperature, the reaction substance is poured into 200 ml of ice-cold water and extracted with ethyl acetate. The organic layer is washed with water and dried over anhydrous sodium sulfate and then the solvent is evaporated under reduced pressure. The residue is treated with ethanolic hydrogen chloride to give 5-o-chlorophenyl-7-ethyl-1-(2-diethylaminoethylcarbamoyl)-2,3-dihydro-1H-thieno[2,3-e][1,4]diazepine dihydrochloride monohydrate as yellow crystals. This product, when recrystallized from a mixture of methanol and ethyl acetate, melts at 150°-151° C with decomposition.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]([NH:26][C:27]3[CH:46]=[CH:45][C:30]([C:31]([N:33]([CH3:44])[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[O:40][CH2:41][CH2:42][OH:43])=[O:32])=[CH:29][CH:28]=3)=[O:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH3:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[C:19]([C:24]([NH:26][C:27]3[CH:28]=[CH:29][C:30]([C:31]([N:33]([CH3:44])[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[O:40][CH2:41][CH:42]=[O:43])=[O:32])=[CH:45][CH:46]=3)=[O:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:16][CH:17]=1
Reactant: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3OCCO)cc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3OCC=O)cc2)cc1
Reaction time: 0.17 h
Yield: 95.9 %

Procedure:
To a solution of oxalyl chloride (174 mg) in dichloromethane (15 ml) was added dimethyl sulfoxide (107 mg) at −78° C. and the solution was stirred at the same temperature for 10 minutes. A solution of 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-[2-(2-hydroxyethoxy)phenyl]benzamide (440 mg) in dichloromethane (5 ml) was added to the mixture at −78° C. After being stirred at −78° C. for 20 minutes, triethylamine (0.51 ml) was added to the mixture at the same temperature and the cooling bath was removed. The mixture was stirred at ambient temperature for 3 hours and the solution was washed successively with 1N hydrochloric acid, water and brine. The organic solution was dried over magnesium sulfate and the solvent was evaporated in vacuo to give 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-[2-(formylmethoxy)phenyl]benzamide (420 mg) as an amorphous.
Reaction SMILES: Cl[CH:2]([C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])=[CH:34][CH:33]=1)[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:5][CH:4]=1.[CH2:61]([NH2:68])[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1.C(N(C(C)C)C(C)C)C>C(Cl)(Cl)Cl>[CH2:61]([NH:68][CH:2]([C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])=[CH:34][CH:33]=1)[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:5][CH:4]=1)[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1
Reactant: NCc1ccccc1
Reactant: CCCCCCCCCCCCCCCCCCCCCCOc1ccc(C(Cl)c2ccc(OCCCCCCCCCCCCCCCCCCCCCC)cc2)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCCCCCCCCCCCCCOc1ccc(C(NCc2ccccc2)c2ccc(OCCCCCCCCCCCCCCCCCCCCCC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
To chloro-bis(4-docosyloxyphenyl)methane (75.9 mg, 89.1 μmol) were added chloroform (1 ml), benzylamine (29.1 μl, 267 μmol), and N-ethyldiisopropylamine (45.7 μl, 267 μmol), and the mixture was stirred at room temperature overnight. The reaction mixture was warmed to 50° C. and stirred for 1 hour. The mixture was cooled to room temperature again, and washed successively with 0.5N hydrochloric acid, 10% aqueous sodium hydrogen carbonate and 20% brine. The organic layer was dehydrated with anhydrous sodium sulfate, chloroform was evaporated, and the residue was precipitated with methanol to give N-benzyl-[bis(4-docosyloxyphenyl)]methylamine (72 mg, 87%).